Corinne Fisher

A diffusion-based quantification technique for assessment of sacroiliitis in adolescents with enthesitis-related arthritis

Objective: To investigate the use of a quantitative diffusion-weighted imaging (DWI) tool for measuring inflammation of the sacroiliac joints (SIJs) in enthesitis-related arthritis (ERA). Methods: A retrospective study was performed with institutional review board approval. Subjects were adolescents who had undergone MRI of the SIJs since January 2010. 10 patients with a clinical diagnosis of ERA and 10 controls with a clinical diagnosis of mechanical back pain were assessed. Axial T1 weighted, short tau inversion recovery (STIR) and DWI (b-values 0, 50, 100, 300 and 600 mm2 s−1) images were acquired. Apparent diffusion coefficient (ADC) maps were generated using a monoexponential fit. On each of four slices, two to three linear regions-of-interest were placed on each joint. Normalized ADC (nADC) values were defined as joint ADC divided by a reference ADC derived from normal sacral bone. STIR images were scored using a modification of an established technique. The correlation between nADC values and STIR scores was evaluated using Spearmans rank correlation. Results: Mean nADC values were significantly higher in cases than in controls (p = 0.0015). There was a strong correlation between STIR scores and nADC values (R = 0.85). Conclusion: ADC values are significantly increased in inflamed SIJs compared with controls. There is a good correlation between this diffusion-based method and STIR scores of inflammation. Advances in knowledge: We have described and provisionally validated a method for quantifying the severity of inflammation in the SIJs in ERA using ADC measurements. This method is quick, is reproducible and could potentially be automated.

Diffusion-weighted imaging is a sensitive biomarker of response to biologic therapy in enthesitis-related arthritis.

Objective. The aim was to evaluate diffusion-weighted imaging (DWI) as a tool for measuring treatment response in adolescents with enthesitis-related arthropathy (ERA). Methods. Twenty-two adolescents with ERA underwent routine MRI and DWI before and after TNF inhibitor therapy. Each patient’s images were visually scored by two radiologists using the Spondyloarthritis Research Consortium of Canada system, and sacroiliac joint apparent diffusion coefficient (ADC) and normalized ADC (nADC) were measured for each patient. Therapeutic clinical response was defined as an improvement of ⩾ 30% physician global assessment and radiological response defined as ⩾ 2.5-point reduction in Spondyloarthritis Research Consortium of Canada score. We compared ADC and nADC changes in responders and non-responders using the Mann–Whitney–Wilcoxon test. Results. For both radiological and clinical definitions of response, reductions in ADC and nADC after treatment were greater in responders than in non-responders (for radiological response: ADC: P < 0.01; nADC: P = 0.055; for clinical response: ADC: P = 0.33; nADC: P = 0.089). ADC and nADC could predict radiological response with a high level of sensitivity and specificity and were moderately sensitive and specific predictors of clinical response (the area under the receiver operating characteristic curves were as follows: ADC: 0.97, nADC: 0.82 for radiological response; and ADC: 0.67, nADC: 0.78 for clinical response). Conclusion. DWI measurements reflect the response to TNF inhibitor treatment in ERA patients with sacroiliitis as defined using radiological criteria and may also reflect clinical response. DWI is more objective than visual scoring and has the potential to be automated. ADC/nADC could be used as biomarkers of sacroiliitis in the clinic and in clinical trials.

Inflammatory changes of the lumbar spine in children and adolescents with enthesitis-related arthritis: magnetic resonance imaging findings.

To describe and profile abnormalities of the lumbar spine in a cohort of patients with enthesitis‐related arthritis (ERA) as compared to a control group of adolescents with mechanical back pain.

Enthesitis related arthritis- 2 distinct clinical phenotypes?

Background Enthesitis related arthritis (ERA) is the subtype of juvenile idiopathic arthritis (JIA) as defined by the International League of Associations for Rheumatology (ILAR) classification (2004). Asymmetrical lower limb arthritis and enthesitis are said to be prominent early features with axial inflammation a late feature. In our cohort of patients with ERA we observed this was often not the casewith axial inflammation occurring early and the emergence of 2 distinct clinical phenotypes.

Low back pain in adolescents with inflammatory arthritis can be due to lumbar spine apophyseal joint inflammation, and this requires contrast enhancement for adequate assessment: comment on the article by Weiss et al

To the Editor: We read with interest the recent report by Weiss et al on magnetic resonance imaging (MRI) for detection of inflammatory sacroiliitis in children (1). We agree with the authors that MRI of the sacroiliac joints in children and adolescents does not require the use of intravenous gadolinium contrast enhancement for the diagnosis of sacroiliitis. However, low back pain in patients with inflammatory spondyloarthritis (SpA) can be due to causes other than sacroiliitis. In our experience at the Arthritis Research UK Centre for Adolescent Rheumatology (www.centre-for-adolescentrheumatology.org), we have demonstrated that 38% of 58 adolescent patients (median age 16.5 years) with enthesitis-related arthritis (as defined by the revised International League of Associations for Rheumatology classification criteria for juvenile idiopathic arthritis subtypes) (2) had apophyseal joint inflammation of the lumbar spine, and this was seen with or without concurrent sacroiliitis (3); in 23% of these patients with apophyseal joint synovitis there was no MRI evidence of definite sacroiliitis. Apophyseal joint inflammation was seen only on contrast-enhanced scans in a large proportion of the patients (70% of those with apophyseal joint inflammation). Even among patients with the most severe apophyseal joint changes (grade 3: synovitis and bone marrow edema), inflammation was visualized on water-sensitive images in only half the cases, as compared to postcontrast scans. Furthermore, sacroiliitis and apophyseal joint synovitis can change independently of one another (4). Persistent or deteriorating lumbar apophyseal joint synovitis can occur in patients with improving sacroiliitis and could account for persistent inflammatory pain in patients in whom disease would appear to be resolving if only the sacroiliac joints were examined. We acknowledge that more research needs to be undertaken to define the association between inflammatory lower back pain, sacroiliitis, and apophyseal joint synovitis in children and adolescents with enthesitis-related arthritis/childhoodonset SpA. Hence, the report by Weiss et al is a welcome addition to the evidence base in the study of this important area. However, given our findings that have been recently reported (3), we propose that clinicians use a low threshold for including imaging of the lumbar spine as an addition to the MRI scan of the sacroiliac joints in all young patients with inflammatory back pain, both at the time of diagnosis and during disease followup to monitor response. If the lumbar spine is imaged, then contrast enhancement to facilitate adequate assessment of the spinal component of this inflammatory disease is required. Timothy P. Bray, MBBChir Kanimozhi Vendhan, MBBS, DMRD, FRCR University College London Corinne Fisher, MBBCh Debajit Sen, FRCP, DCH Yiannis Ioannou, MBBS, BMedSci, PhD, FRCP University College London and Arthritis Research UK Centre for Adolescent Rheumatology Margaret A. Hall-Craggs, FRCR, MD University College London London, UK

Juvenile arthritis disease activity score is a better reflector of active disease than the disease activity score 28 in adults with polyarticular juvenile idiopathic arthritis

A considerable proportion of children with polyarticular juvenile idiopathic arthritis (polyJIA) experience active disease into adulthood.1 However, there is no validated disease activity measure for adults with polyJIA, and they are often assessed using the disease activity score 28 (DAS28). DAS28 is validated in adults with rheumatoid arthritis (RA), and determines qualification for biological drugs in the UK and other countries.2 ,3 In contrast to the juvenile arthritis disease activity score (JADAS),4 DAS28 does not fully evaluate the pattern of joint involvement often observed in polyJIA. In this study, we compared DAS28 with JADAS-10 in adolescents and adults with polyJIA. Tender and swollen joint counts out of 28, active joint count of all joints up to a maximum of 10, patient/parent and physician global assessment visual analogue scales were collected from clinics in patients aged ≥10 years with polyJIA (International League of Associations for Rheumatology classification criteria for rheumatoid factor-negative (RhF-ve) or rheumatoid factor-positive (RhF+ve) polyJIA). Erythrocyte sedimentation rate (ESR) values were taken within 30 days before or after assessment. When unavailable, values were taken within 3 months before or after, provided the patient remained stable between the ESR test and assessment. When unavailable within these time periods, patients were excluded from …

Sacroiliac Joint Ankylosis In Young Spondyloarthritis Patients Receiving Biologic Therapy: Observation of Serial MRI scans

To assess the temporal relationship between initiating biologic therapy and magnetic resonance imaging (MRI) scores of inflammation and structural damage in young patients with spondyloarthritis.

FRI0595 The beach tool: a quantitative mri-based method for measuring oedema and fat metaplasia in spondyloarthritis

Background Magnetic resonance imaging (MRI) is an important part of diagnostic pathways in spondyloarthritis (SpA), and can be used to stratify patients and assess severity. However, measurements of the burden of inflammation currently rely on qualitative assessment, which is subjective and time-consuming thus impractical for clinical practice. There is a need for a more objective, faster method for measuring inflammation and damage with potential for automation, and quantitative MRI is a candidate tool. Objectives We aimed to provide proof-of-principle for the BEACH (Bone OEdema and Adiposity quantification with Apparent diffusion coefficient and Chemical shift imaging with histograms) tool, which quantifies bone marrow oedema and fat metaplasia – features of active and chronic inflammation – in the SIJs. Methods Fifty-three patients aged 12–24 years with either SpA or mechanical back pain were recruited prospectively, and underwent quantitative MRI consisting of diffusion weighted imaging (DWI) and fat fraction (FF) mapping,2,3 and conventional MRI scans. Apparent diffusion coefficient (ADC) and FF maps were assessed using the BEACH tool, which automatically propagates ROIs on subchondral bone after the observer defines the SIJ. Pixel values were analysed to derive the histographic parameters for ADC and FF: median, 10th, 25th, 75th and 90th percentiles (denoted ADC10, ADC25, FF10, FF25, etc), and phigh and plough (the proportion of high and low value pixels respectively). Conventional MRI scans were assessed using visual scoring.4 Patients were deemed to have active inflammation if their inflammation score was ≥2, and to have fat metaplasia if this score was ≥3. Quantitative measurements were compared between inflamed and non-inflamed SIJs. Results Use of the BEACH tool is demonstrated in figure 1(a)-(f). Example ADC histograms are shown in (g),(h). ADC75, ADC90, and phigh(ADC) were significantly increased in inflamed SIJs (P=0.041, 0.006 and 0.003 respectively), although median ADC values did not differ significantly between inflamed and uninflamed joints (P=0.31). Diagnostic performance was superior for histographic parameters (AUC=0.59, 0.67 and 0.69) than for the median (AUC=0.54) Median FF, FF75, FF90 and phigh(FF) were all significantly increased in SIJs with fat metaplasia compared to those without (all p<0.0001). Diagnostic performance was superior for histographic parameters FF75, FF90 and phigh(FF) (AUC=0.89, 0.92 and 0.92) than for the median (AUC=0.87). Conclusions ADC and FF measurements can differentiate between inflamed and non-inflamed SIJs, and between joints with and without fat metaplasia. Compared to simple averages such as the median, histographic parameters can increase diagnostic performance for detecting inflammation and fat metaplasia. There is minimal subjectivity associated with ROI placement using the BEACH tool, which can potentially make inflammation scores more reproducible. References [1] Vendhan K, et al. Br J Radiol. 2016. [2] Bray TJP, et al. Rheumatol. 2017. [3] Bray TJP, et al. Magn Reson Med. 2017. [4] Maksymowych WP, et al. Arthr Care Res. 2005. Acknowledgements Funding: TJPB:ARUK grant 21369;MHC, UCLH BRC;CC, CF:ARUK. Disclosure of Interest None declared

FRI0193 Prognostic markers in axial spondyloarthritis (PROMISE) – cross sectional evaluation of serum biomarkers in axspa, mechanical back pain and healthy controls

Background In recent years there has been increasing interest in biomarkers in axial spondyloarthritis, for diagnosis, disease prognostication, and to monitor treatment effect.1 2 Many biomarkers have been evaluated, but the role each of these plays and how they may interact is unclear. Objectives Our aim was to evaluate a broad panel of serum biomarkers in a large mixed cohort of patients, with Ankylosing Spondylitis (AS), non radiographic axial Spondyloarthritis (nr-axSpA), mechanical back pain (MBP) and healthy controls (HC), in order to identify any potential biomarkers for diagnosis by assessing the differences between the groups. Methods Cross sectional evaluation of 46 serum biomarkers was undertaken by Myriad RBM using multiplexed immunoassays of Multi-Analyte Panels, in a cohort of patients from a tertiary referral centre, consented as part of the Bath Spondyloarthritis BioBank. Validated patient reported outcomes (including BASDAI, BASFI) and BASMI were completed. 50 HC blood samples were also collected at University College London for biomarker analysis. Results 331 patients were included in the study, of which 59.5% AS, 8.2% nr-axSpA, 15.7% mechanical back pain, 15.1% HC. 64.7% were male, mean age 44.2 years (SD 16.6), mean disease duration in the AS group of 22.4 years (SD 13.6) with 84% HLA B27 positive. IL1 alpha and beta, IL1 receptor antagonist, IL2, 3, 4, 5, 7, 10, 15, 17, IL12 subunit p70, factor VII, GMCSF, IFN gamma, MMP9, TNF beta were the only biomarkers not to show statistical differences across the diagnostic groups (table 1.). 12 biomarkers showed a statistical difference between genders (table 1, column 1, p value significance indicated with *<0.05, **<0.01 using Mann Whitney U, in addition to Factor VII*).Abstract FRI0193 – Table 1 Statistically significant serum biomarker results by diagnosis Conclusions Serum biomarkers have been shown to vary with gender and diagnosis. Further work is planned to evaluate their relationship to disease activity using outcome measures such as the BASDAI, and radiographic scoring, to better understand the role of each factor and combination of factors, and any causal link. References [1] Maksymowych WP. An update on biomarker discovery and use in axial spondyloarthritis. Expert Rev Mol Diagn [Internet]. 2017Nov;217(11):965–74. [cited 2017 Dec 7]. Available from: https://www.tandfonline.com/doi/full/10.1080/14737159.2017.1381562 [2] Reveille JD. Biomarkers for diagnosis, monitoring of progression, and treatment responses in ankylosing spondylitis and axial spondyloarthritis. Clin Rheumatol [Internet]2015Jun 5;34(6):1009–18. [cited 2017 Jul 10]. Available from: http://link.springer.com/10.1007/s10067-015-2949-3 Acknowledgements This study was undertaken as part of an ongoing piece of work that is being funded by Celgene. Disclosure of Interest None declared

OP0056 IL-23P19 is up-regulated in monocyte-derived macrophages from HLA B27 positive patients with enthesitis related arthritis

Background Enthesitis related arthritis (ERA) is an HLAB27-associated subtype of JIA most similar to the adult spondyloarthropathies (SpA). The innate immune system, intracellular stress response (the unfolded protein response (UPR)) and IL23/IL17 pathway are strongly implicated in the pathogenesis of adult SpA. However, these systems remain relatively unexplored in ERA. Objectives To compare levels of the IL23 subunit, IL23p19, produced by monocyte-derived macrophages (MDMs) in the presence of lipopolysaccharide (LPS) and an inducer of the UPR (tunicamycin (TM)) from patients with ERA and healthy controls. Other pro-inflammatory cytokines and markers of the UPR were also studied. Methods Peripheral blood monocytes isolated from 30 patients with ERA (20 HLAB27 positive, 10 HLAB27 negative, median age 16yrs 4mths, median disease duration 3yrs 9mths, M:F 7:1) and 16 age and gender-matched healthy controls were differentiated in vitro with macrophage-colony stimulating factor. Cells were treated with IFNγ and then stimulated with LPS alone or LPS with TM for 24 hours. Pro-inflammatory cytokines and markers of the UPR were measured by expression of mRNA using qPCR and normalised against GAPDH. Results IL23p19 expression was higher in MDMs from HLAB27 positive patients with ERA compared to healthy controls treated with LPS [median relative expression 384.7 (IQR 179.2–1340) vs 90.5 (49.9–455.9), p=0.02]. With the addition of the UPR inducer, TM, enhanced IL23p19 mRNA expression was also seen in HLAB27 positive patients compared to those who were HLAB27 negative and healthy controls [median relative expression 608.9 (IQR 282–3286) vs 283.0 (IQR 20.1–928.2) vs 195.1 (IQR 9.8–853.7); p=0.02]. When the groups were divided in to males and females, significantly higher IL23p19 expression was seen in MDMs treated with LPS from male HLAB27 positive patients with ERA compared to male healthy controls [661.7 (IQR 169.7–1531) vs 78.3 (39.01–139.6), p=0.0095] (figure 1). This was also the case for MDMs treated with LPS and TM [537.5 (IQR 295.3–3054) vs 93.05 (IQR 2.7–1109); p=0.02]. To investigate the effect of UPR induction on IL23p19 mRNA expression, percentage increase was calculated for each patient between MDMs treated with LPS alone and MDMs treated with LPS and TM. Interestingly, median percentage increase for HLAB27 positive patients with ERA was 63% but a decrease was seen in IL23p19 mRNA expression for in HLAB27 negative patients (-3.8%) with the addition of TM. When HLAB27 positive patients not oh TNF inhibitors were compared to those on treatment, the median percentage increase between LPS and LPS + TM treated MDMs was significantly modulated [78.7% vs 10.1%, p-0.049]. mRNA expression for other pro-inflammatory cytokines including TNF, IL1 and IL6, in addition to markers of the UPR (XBP1, CHOP and BiP) demonstrated no significant differences between patients and healthy controls. Conclusions Expression of IL23p19 mRNA in MDMs is significantly enhanced in HLAB27 positive patients with ERA. In this group, the induction of the UPR appears to further enhance IL23p19 expression but this effect is modulated by treatment with TNF inhibitors. These results suggest a potential role for IL23 and the UPR in the pathogenesis of ERA, particularly in those who are HLAB27 positive and may have implications for treatment stratification, indicating a subgroup of patients who may respond to IL23 blockade. Disclosure of Interest None declared